Dosage form for treating dysthymia

ABSTRACT

A dosage form is provided for administering a drug of the formula ##STR1## to a patient to produce an anxiolytic benefit in the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 07/842,682filed Feb. 27, 1992 now U.S. Pat. No. 5,185,158 issued Feb. 9, 1993.This application is copending with an application identified as ARC 2021CIP 1 now U.S. Ser. No. 07/942,899 filed Sep. 10, 1992 pending. Theseapplications are assigned to the ALZA Corporation of Palo Alto, Calif.and benefit is claimed of their filing date.

FIELD OF THE INVENTION

This invention pertains to a novel and useful dosage form comprising thetherapeutic drug represented by the general formula: ##STR2## Theinvention concerns also a method for treating depressive disorders byadministering the dosage form for delivering the drug of the generalformula to a patient in need of antidepressive therapy. The inventionrelates also to novel compositions comprising the general formula, whichcompositions are useful for manufacturing the dosage form.

BACKGROUND OF THE INVENTION

A health need exits for a dosage form comprising the therapeuticallyactive drug of the general formula (1): ##STR3## especially for a dosageform that exhibits an essentially zero order release rate of formula (1)over a long period of time. In formula (1) A is a member selected fromthe group consisting of an oxygen atom, a methylene group, and anethylene group; ( ) in the six-membered carbocycle ring comprises amember selected from a single bond and a double bond; R is a phenylgroup optionally substituted with a member selected from the groupconsisting of halogen, an alkyl of 1 to 4 carbons, an alkoxy of 1 to 4carbons, a trifluoromethyl, a 2-pyridyl group and a 2-pyrimidinyl group,and wherein n is an integer of 3 or 4, the base, and thepharmaceutically acceptable salt thereof. The drug can be also in theexo and the endo form thereof.

A presently preferred drug embraced by formula (1) is represented byformula (2). ##STR4## The drug depicted by formula (2) is known also astandospirone, or by the name 4,7-methano-1H-isoindole-1,3(2H)-dione,hexahydro-2[4-[-(2-pyrimidinyl)-1-piperazinyl]butyl]-(3aα,4β,7aα)-2-hydroxy-1,2,3-propanetricarboxylate(1:1) or asN-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl-2,3-norbornanedicarboximide.The drugs of both formulae are taught in prior art patents U.S. Pat.Nos. 4,507,303; 4,543,355; 4,598,078 and 5,011,841. The beneficial drugsof the formulae are administered by the prior art in rapid releasedosage forms, such as tablet, capsule, syrup and suspension. With suchrapid release forms, the drug is administered by repeated administrationto produce a therapeutic level.

Generally, for rapid release dosage forms, as known to the prior artalso as instant release dosage forms, the release rate profile followsthe cube root law, that is, the release rate decreases with time, Inter.J. Pharm., Vol. 62, pp 143-151, 1990. This release rate pattern providesunpredictable therapy and it is often accompanied by a period of time,when the patient is not receiving the drug. A critical health needexists for a zero order dosage form that overcomes the shortcomingsknown to the prior art. A zero order dosage form provides drugcontinuously to the patient for constant therapy for better health. Adosage form made with zero order drug delivery properties, provides drugat a controlled rate as a zero order plot of the rate of release of drugversus time shows an essentially straight line that indicates the rateof release is independent of time. A dosage form, according to thepresent invention, that provides for the zero order administration ofdrugs of formulae of (1) and (2), would represent a major advancement tothe drug delivery art, because the controlled and sustained zero orderrelease of drug in a known and uniform dose over a long period of timereinforces better therapy.

In light of the above presentation, it will be evident to those versedin the dispensing art, that a pressing need exists for a dosage formpossessing a zero order rate of release that can deliver the valuabledrug of formulae 1 and 2 for its therapy. The pressing need exists for adosage form having a zero order rate of release, which zero order isgenerated by osmotic activity, while simultaneously maintaining thephysical and chemical integrity of the osmotic dosage form during thedrug delivery period.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a dosage form for delivering, at anessentially zero order rate of release, the drug of formulae (1) and (2)to a patient in need of formulae (1) and (2) drug therapy.

Another object of the present invention is to provide a zero orderdosage form that substantially overcomes the deficiencies associatedwith the prior art.

Another object of the present invention is to provide a dosage form foradministering formulae (1) and (2) drug at a zero order rate of releasedose over a prolonged period of time for treating depressive disorders.

Another object of the present invention is to provide a dosage form thatmakes available zero order sustained and controlled formula (2)tandospirone therapeutic activity for anxiolytic therapy.

Another object of the invention is to provide a novel dosage formmanufactured as an osmotic dosage form that can administer a drugembraced by formula (1) comprising tandospirone at a zero order rate toa biological receptor site to produce the desired formula (1) comprisingtandospirone pharmaceutical effects.

Another object of the present invention is to provide a dosage formmanufactured as an osmotic dosage form that substantially reduces and/orsubstantially eliminates the unwanted influences of the gastrointestinalenvironment of use and still provides controlled administration offormulae (1) and (2) as exemplified by tandospirone over time.

Another object of the present invention is to provide an osmoticoperated dosage form that maintains its physical and chemical integritywhile producing an internal high osmotic pressure during the delivery oftandospirone.

Another object of the present invention is to provide a dosage formadapted for oral administration of tandospirone, which dosage formcomprises a first tandospirone composition and a second push compositionthat act together for the rate controlled administration to a patientover time.

Another object of the present invention is to provide a composition ofmatter comprising tandospirone, which composition is useful formanufacturing a dosage form.

Another object of the present invention is to provide a completepharmaceutical regimen comprising a composition comprising tandospironethat can be dispensed from an osmotic delivery device, the use of whichrequires intervention only initiation and possibly for the terminationof the regimen.

Another object of the invention is to provide a method for treatingdepressive disorder comprising administering an antidepressive effectivedose of tandospirone from a zero order dosage form, to a warm-bloodedanimal.

Another object of the invention is to provide the use of a dosage formfor administering tandospirone from a dosage form at an osmoticallypowered rate over time, wherein the tandospirone is selected from thegroup consisting of a base, a salt, an endo and an exo form.

Other objects, features and advantages of the invention will be moreapparent to those versed in the dispensing arts, from the followingdetailed specification, taken in conjunction with the drawings and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In these drawing figures, which are not drawn to scale, but are setforth to illustrate various embodiments of the invention, the drawingfigures are as follows:

Drawing FIG. 1 is a view of a dosage form designed and shaped foradministering orally the drugs of formulae (1) and (2) includingpresently preferred tandospirone to biological, gastrointestinalreceptors of drugs of formulae (1) and (2) including tandospirone;

Drawing FIG. 2 is an opened-view of the dosage form of drawing FIG. 1,for illustrating the total structure of the dosage form;

Drawing FIGS. 3a and 3b are graphs that depict the dose of tandospironereleased per hour over a prolonged period of twenty-four hours and thecumulative dose released from the dosage form;

Drawing FIG. 4 is a graph depicting the cumulative amount oftandospirone released at a controlled rate from a different dosage formprovided by the invention; and,

Drawing FIG. 5 depicts the release from two different dosage formscomprising different drug layers from the dosage forms.

In the drawing figures and in the specification like parts in relateddrawing figure are identified by like numbers. The terms appearingearlier in the specification and in the description of the drawings, aswell as embodiments thereof, are further described elsewhere in thedisclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which drawing figures arean example of the dosage forms provided by this invention, and whichexample is not to be construed as limiting the invention, one example ofthe dosage form is illustrated in drawing FIG. 1 and designated by thenumeral 10. In drawing FIG. 1, dosage form 10 comprises a body member 11comprising a wall 12 that surrounds and encloses an internalcompartment, not seen in drawing FIG. 1. Wall 12 keeps its physicalintegrity and structure in the presence of osmotic and hydrodynamicpressure generated within dosage form 10 during operation of dosage form10. Dosage form 10 comprises at least one exit means 13 for connectingthe interior of dosage form 10 with the exterior environment of use.

In drawing FIG. 2, dosage form 10, manufactured as an osmotic dosageform, is seen in opened view. In drawing FIG. 2, dosage form 10comprises body 11, wall 12 that is sectioned at 14, depicts wall 12 thatsurrounds and defines an internal compartment 15. Wall 12 comprises atleast one exit means 13 that connects compartment 15 with the exteriorof dosage form 10. Dosage form 10 can comprise more than one exit means13.

Wall 12 of dosage form 10 comprises a composition that is permeable tothe passage of an exterior fluid present in the fluid environment ofuse, and the wall-forming composition is substantially impermeable tothe drug of formulae (1) and (2), and to other components present incompartment 15. The composition is semipermeable, it is nontoxic andsubstantially inert. The composition maintains its physical and chemicalintegrity, that is, it does not change its chemical nature,independently of the structure of wall 12. Wall 12 comprises from 70weight percent, (wt %), to 100 wt % of a cellulose wall-forming polymer.The polymer comprises a member selected from the group consisting ofcellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate and cellulose triacetate. In anotheroperative manufacture, wall 12 comprises additionally from 0 wt % to 25wt % of a cellulose ether selected from the group consisting ofhydroxypropylcellulose and hydroxypropylmethylcellulose; and from 0 wt %to 15 wt % of a polyethylene glycol. The total weight percent of allcomponents comprising wall 12 is equal to 100 wt %.

Dosage form 10, as seen in drawing FIG. 2, in compartment 15 comprises adrug layer 16 and a push layer 17. Drug layer 16 and push layer 17 acttogether, during operation of dosage form 10, for the delivery of drugof formulae (1) and (2), as exemplified by tandospirone, to a patient inneed of formulae (1) and (2) therapy. Drug layer 16 and push layer 17also act with wall 12 for the controlled rate of release of drug offormulae (1) and (2) over time.

Drug layer 16 comprises 5 wt % to 80 wt % of a drug selected fromformula (1) as exemplified by formula (2) which depicts tandospirone,and its therapeutically acceptable salts, identified by dots 18. Thetherapeutic dose of a formula (1) drug as represented by tandospirone 18in a single dosage form 10, expressed in milligrams, (mg), is from 1 mgto 750 mg. Individual dosage form 10 comprises 2, 5, 10, 40, 50, 80,120, 160, 250, 300, 500 and 750 mg of drug for administering in a singledose, or in more than one dose. The pharmaceutically acceptablenon-toxic salts useful for the present purpose comprise a memberselected from the group consisting of inorganic, organic, hydrochloric,hydrobromic, sulfuric, phosphoric, acetic, propionic, butyric, tartaric,citric, maleic, fumaric, lysine, succinic, palmitic, and glycine salts.

Drug layer 16 comprises additionally a polymer 19, depicted by a wavyline, for transporting drug 18 from dosage form 10. Polymer 19, in onemanufacture comprises the structure (--O--CH₂ CH₂ --)_(n) wherein n is apositive whole number of 4500 to 5000. Representation of the polymer 19is a poly(oxyethylene) of approximate average molecular weight of 2×10⁵.Drug layer 16, comprises in another manufacture a polymer compositioncomprising a first polymer and a second polymer blended together tofunction as a unit polymer 19 comprising drug 18. The first polymercomprises the polymer described immediately above of the structure--(O--CH₂ CH₂ --)_(n), wherein n is a whole number of 6500 to 7500 asrepresented by poly(oxyethylene) of the approximate average molecularweight of 3×10⁵. In the polymer composition, the concentration of thefirst polymer is 20 to 50 wt % and the composition of the second polymeris 2 to 40 wt %, with the proviso that, when the concentration of thesecond polymer exceeds 9 wt %, that is, from 9 to 40 wt %, dosage form10 is manufactured with at least two exits to prevent bursting of dosageform 10. The concentration of the first and second polymer, whenpresented together in dosage form 10, is 35 to 80 wt %. Polymer 19,present as a single polymer, or as a first and second polymer pair,effectively transports, in both manufacture, drug 18 from dosage form10, and they release drug 18 of formulae (1) and (2) to a drug receptorfor its therapy. It is unexpected polymer 19, in both manufactures, canperform its housing-transporting-releasing-compositional functions as acomplex drug composition comprising the drug of formulae (1) and (2)essentially-free of any bonding of drug 18 to polymer 19. Drug layer 16comprises optionally from zero wt % to 3 wt % of a lubricant 20 such asmagnesium stearate or calcium stearate; from 0 to 20 wt % of anosmotically active compound 21 such as a member selected from the groupconsisting of an inorganic salt, an organic salt, a compound containingan amino group, a carbohydrate, an acid and an ester; and 0 wt % to 4 wt% of an anti-oxidant for imparting stability to the drug composition 16,said anti-oxidant comprising a member selected from the group consistingof ascorbic acid, 2,3-butyl hydroxyanisole, mono-tertiary butylhydroquinone, and butylated hydroxytoluene; and 0 to 10 wt % of adrug-powder coating agent poly(vinylpyrrolidone) having a 3,000 to1,250,000 molecular weight. The total weight percent of all componentsin drug 16 is equal to 100 wt %.

Second layer 17 comprises 50 wt % to 75 wt % of a polymer 22 comprisingthe repeating molecular unit --(--O--CH₂ CH₂ --)--_(n), wherein n is apositive whole number of 90,000 to 230,000. Representative of polymer 22embraced by the repeating molecular unit is a poly(alkaline oxide)comprising poly(ethylene oxide) comprising an approximate averagemolecular weight of 4×10⁶ to 10×10⁶. Polymer 22 provides unexpectedoperating advantages as the polymer maintains its chemical compositionduring operation as it imbibes an external aqueous fluid includingbiological fluid while simultaneously pushing drug layer 16 from dosageform 10 essentially-free of substantially mixing with drug layer 16.Second layer 17 comprises also 15 wt % to 35 wt % of an osmoticallyactive compound 23, represented by small squares. Representation ofosmotically effective compounds comprises salts, esters, carbohydratesand acids, such as a member selected from the group consisting ofmagnesium sulfate, magnesium chloride, sodium chloride, lithiumchloride, potassium sulfate, sodium sulfate, lithium sulfate, potassiumchloride, ammonium chloride, potassium lactate, mannitol, urea,inositol, magnesium succinate, tartaric acid, raffinose, sorbitol,sucrose, fructose, glycose and the like. Second layer 17 comprises also0.1 wt % to 20 wt % of a cellulose ether 24 represented by smallcircles. Representative of cellulose ethers comprise a member selectedfrom the group consisting of hydroxypropylcellulose andhydroxypropylmethylcellulose having a molecular weight of 9,000 to22,500. The composition comprises 0 wt % to 5 wt % of a lubricant suchas stearic acid, magnesium stearate, calcium stearate, calcium oleate,oleic acid and caprylic acid. The polymers disclosed herein arecommercially available from the Union Carbide Corporation, SouthCharleston, W. Va.

The expression, "exit means 13", as used herein, comprises means andmethods suitable for the metered release of the therapeutic drug 18 fromcompartment 15 of dosage form 10. The exit means 13 comprises at leastone passageway, orifice, bore, aperture, pore, porous element, hollowfiber, capillary tube, porous overlay, and porous element that providesfor the osmotic controlled release of drug 17. The expression exit means13 includes a material that erodes or is leached from wall 12 in a fluidenvironment of use to produce at least one osmotic dimensionedpassageway 13 is dosage form 10. Representative materials suitable forforming a passageway, or a multiplicity of passageways comprise aleachable poly(glycolic) acid or poly(lactic) acid polymer in wall 12, agelatinous filament, poly(vinyl alcohol), leachable polysaccharides,salts and oxides. A pore passageway, or more than one pore passagewayscan be formed by leaching a leachable compound, such as sorbitol, fromwall 12. The passageway possessing controlled release dimensions such asround, triangular, square, elliptical, and the like, for the meteredrelease of drug 17 from dosage form 10. Dosage form 10 can be construedwith one or more passageways in spaced apart relationship on a singlesurface or on more than one surface of dosage form 10. Passageways andequipments for forming passageways are disclosed in U.S. Pat. Nos.3,845,770; 3,916,899; 4,063,064; 4,088,864 and 4,816,263. Passagewaysformed by leaching are disclosed in U.S. Pat. Nos. 4,200,098 and4,285,987.

DESCRIPTION OF PROCESSES FOR MANUFACTURING THE DOSAGE FORM OF THEINVENTION

Wall 12 of osmotic dosage form 10 can be formed in one technique usingthe air suspension procedure. This procedure consists in suspending andtumbling the compressed layers in a current of air and wall formingcomposition until a wall is applied to the drug forming compartment. Theair suspensions procedure is well-suited for independently forming thewall. The air suspension procedure is described in U.S. Pat. No.2,799,241; J. Am. Pharm. Assoc., Vol. 48, pages 451 to 459, 1959; andibid. Vol. 49, pages 82 to 84, 1960. Osmotic dosage forms can also becoated with a wall-forming composition in a Wurster® air suspensioncoater, using acetone-water cosolvent, 90:10, wt:wt, using 2.5 to 7 wt %polymer solids. The Aeromatic® air suspension coater using a methylenedichloride methanol cosolvent, 87:13, v:v, also can be used for applyingthe wall. Other wall forming techniques, such as pan coating, can beused for providing the dosage form. In the pan coating system, wallforming compositions are deposited by successive spraying of thecomposition on the bilayered compartment, accompanying by tumbling in arotating pan. A larger volume of cosolvent can be used to reduce theconcentration of polymer solids to produce a thinner wall. Finally, thewall coated compartments are laser or mechanically drilled and dried ina forced air oven at 30° C. to 50° C. for a week to free the dosage formof solvent. Generally, the walls formed by these techniques have athickness of 2 to 20 mils (0.051 to 0.51 mm) with a presently preferredthickness of 2 to 6 mils (0.051 to 0.15 mm).

Dosage form 10 of the invention is manufactured by standardmanufacturing techniques. For example, in one manufacture, thebeneficial drug and other ingredients comprising the first layer facingthe exit means are blended and pressed into a solid layer. The drug andother ingredients can be blended also with a solvent and mixed into asolid or semisolid formed by conventional methods such as ball-milling,calendering, stirring or rollmilling and then pressed into a preselectedshape. The layer possesses dimensions that correspond to the internaldimensions of the area the layer is to occupy in the dosage form and italso possesses dimensions corresponding to the second layer for forminga contacting arrangement therewith. Next, the osmopolymer layer isplaced in contact with the drug layer. The layering of the drug layerand the osmopolymer layer can be fabricated by conventionalpress-layering techniques. Finally, the two layer compartment formingmembers are surrounded and coated with an outer wall. A passageway islaser drilled through the wall to contact the drug layer, with thedosage form optically oriented automatically by the laser equipment forforming the passageway on the preselected surface.

In another manufacture, dosage form 10 is manufactured by the wetgranulation technique. In the wet granulation technique, the drug andthe ingredients comprising the first layer are blended using an organicor inorganic solvent, such as isopropyl alcohol-methylene dichloride80/20 v/v as the granulation fluid. Other granulating fluid, such aswater or denatured alcohol 100%, can be used for this purpose. Theingredients forming the first layer are individually passed through a 40mesh screen and then thoroughly blended in a mixer. Next, otheringredients comprising the first layer are dissolved in a portion of thegranulation fluid, such as the cosolvent described above. Then, thelatter prepared wet blend is slowly added to the drug blend withcontinual mixing in the blender. The granulating fluid is added until awet blend is produced, which wet mass then is forced through a 20 meshscreen onto oven trays. the blend is dried for 18 to 24 hours at 25° C.to 40° C. The dry granules are screened then with a 16 mesh screen.Next, a lubricant is passed through an 60 mesh screen and added to thedry screened granule blend. The granulation is put into milling jars andmixed on a jar mill for 2 to 10 minutes. The first and second layercompositions are pressed into a layered tablet, for example, in aManesty® layer press.

Another manufacturing process that can be used for providing thecompartment-forming composition comprises blending the powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for examplepoly(vinyl-pyrrolidone) in water, is sprayed onto the powders. Thecoated powders are then dried in a granulator. This processcoats-agglomerates all the ingredients present therein while sprayingthe granulating fluid. After the granules are dried, a lubricant such asstearic acid or magnesium stearate is blended as above into the mixture.The granules are pressed then in the manner described above.

The osmotic device of this invention is manufactured in anotherembodiment by mixing a drug with composition forming ingredients andpressing the composition into a solid layer possessing dimensions thatcorrespond to the internal dimensions that correspond to the internaldimensions of the compartment space adjacent to a passageway. In anotherembodiment, the drug and other first composition forming ingredients anda solvent are mixed into a solid, or a semi-solid, by conventionalmethods such as ballmilling, calendering, stirring or rollmilling, andthen pressed into a preselected layer forming shape.

In the manufactures as presented above, the manufacture comprising alayer of a composition comprising an osmopolymer and an optionalosmagent are placed in contact with the layer comprising the drug, andthe two lamina comprising the layers are surrounded with a semipermeablewall. The layering of the first drug composition and the secondosmopolymer optional osmagent composition can be accomplished by using aconventional two-layer tablet press technique. The wall can be appliedby molding, spraying or dipping the pressed shapes into 10 wall formingmaterials. Another and presently preferred technique that can be usedfor applying the wall is the air suspension coating procedure. Thisprocedure consists in suspending and tumbling the two layers in acurrent of air until the wall forming composition surrounds the layers.The air suspension procedure is described in U.S. Pat. No. 2,799,241; J.Am. Pharm. Assoc., Vol. 48, pp 451-459 (1979); and, ibid, Vol. 49, pp82-84 (1960). Other standard manufacturing procedures are described inModern Plastics Encyclopedia, Vol. 46, pp 62-70 (1969); and inPharmaceutical Science, by Remington, 14th Ed., pp 1626-1979, (1970),published by Mack Publishing Co., Easton, Pa. The dosage forms can bemanufactured by following the teaching in U.S. Pat. Nos. 4,327,725;4,612,008; 4,783,337; 4,863,456; and 4,902,514.

Exemplary solvents suitable for manufacturing the wall, the laminatesand laminae include inert inorganic and organic solvents that do notadversely harm the materials and the final wall of the final laminatedwall. The solvents broadly include members selected from the groupconsisting of aqueous solvents, alcohols, ketones, esters, ethers,aliphatic hydrocarbons, halogenated solvents, cycloaliphatics,aromatics, heterocyclic solvents and mixtures thereof. Typical solventsinclude acetone, diacetone alcohol, methanol, ethanol,isopropyl alcohol,butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane,n-heptane, ethylene glycol monoethyl ether, ethylene glycolmonoethylacetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon chloroform, nitroethane, nitropropane,tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane,cycl-octane, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme,aqueous and nonaqueous mixtures thereof, such as acetone and water,acetone and methanol, acetone and ethyl alcohol, methylene dichlorideand methanol, and ethylene dichloride and methanol.

DETAILED DISCLOSURE OF EXAMPLES PROVIDED BY THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

A dosage form adapted, designed and shaped as an osmotic drug deliverydevice is manufactured as follows: first, 12.5 kg of micronizedtandospirone, 11.25 kg of poly(ethylene oxide) possessing a 200,000molecular weight are added to a Freund Flo-Coater's® bowl, a fluid bedgranulator. The bowl was attached to the coater and granulation processwas initiated for effecting granulation. Next, the dry powders were airsuspended and mixed for 7 minutes. Then, a solution prepared bydissolving 1000 g of poly(vinylpyrrolidone) identified as K29-32 havingan average molecular weight of 40,000, in 15,667 g of water was sprayedfrom 3 nozzles onto the powder. The coating conditions were monitoredduring the process of aqueous poly(vinylpyrrolidone) as follows:solution spray rate of 125 g/min from each nozzle for a total spray rateof 375 g/min; inlet temperature 45° C.; and process air flow of 1000cfm.

The coating process was computerized and automated in cycles. Each cyclecontained 30 seconds of solution spraying followed by two seconds ofdrying and 10 seconds of filter bags shaking to unglue and possiblepowder deposits. At the end of the solution spraying, 16,667 g, thecoated granulated particles were continued with the drying process for25 minutes. The machine was turned off, and the coated granules wereremoved from the Flo-Coater. The coated granules were sized using aFluid Air Mill. The granulation was transferred to a Rotocone®, mixedand lubricated with 250 g of magnesium stearate and mixed with 12.5 g ofbutylated hydroxytoluene.

Next, a push composition is prepared as follows: first, 415.5 g ofpharmaceutically acceptable poly(ethylene oxide) comprising a 7,500,000molecular weight, 150 g of sodium chloride and 6 g of ferric oxideseparately are screened through a 40 mesh screen. Then, all the screenedingredients are mixed with 30 g of hydroxypropylmethylcellulosecomprising a 11,200 molecular weight to produce a homogeneous blend.Next, 300 mg of denatured anhydrous alcohol is added slowly to the blendwith continuous mixing for 5 minutes. The freshly prepared wetgranulation is passed through a 20 mesh screen, allowed to dry at roomtemperature for 16 hours, and again passed through a 20 mesh screen. Thescreened granulation is mixed with 1.5 of magnesium stearate in arollermill for 5 minutes.

Next, the tandospirone drug composition and the push composition arecompressed into bilayered tablets. First, 352 mg of the tandospironecomposition is added to a punch and tamped, then, 175 mg of the pushcomposition is added and the layers are pressed under a pressure head oftwo tons into a 7/16" (1.11 cm) diameter contacting layered arrangement.

The bilayered arrangements are coated with a semipermeable wall. Thewall forming composition comprises 95% cellulose acetate having a 39.8%acetyl content, and 5% polyethylene glycol having a molecular weight of3350. The wall-forming composition is dissolved in an acetone:water(90:10 wt:wt) cosolvent to make a 4% solids solution. The wall formingcomposition is sprayed onto and around the bilayers in a 24" VectorHiCoater.

Next, two 25 mil (0.635 mm) exit passageways are mechanically drilledthrough the semipermeable wall to connect the drug layer with theexterior of the dosage system. The residual solvent is removed by dryingfor 48 hours at 50° C. and 50% humidity. Next, the osmotic systems aredried for 1 hour at 50° C. to remove excess moisture. The dosage formproduced by this manufacture provides 50 wt % tandospirone, 45 wt %poly(ethylene oxide) possessing a 200,000 molecular weight, 4 wt %poly(vinyl pyrrolidone) possessing a 40,000 molecular weight, 0.95 wt %magnesium stearate, and 0.5 wt % butyl hydroxytoluene. The pushcomposition comprises 68.8 wt % poly(ethylene oxide) comprising a7,500,000 molecular weight, 25 wt % sodium chloride, 5 wt %hydroxypropylmethylcellulose possessing 11,200 molecular weight, 1.0 wt% ferric oxide and 0.2 wt % magnesium stearate. The semipermeable wallcomprises 95 wt % cellulose acetate comprising a 39.8 % acetyl content,and 5.0 wt % polyethylene glycol comprising a 3350 molecular weight. Thedosage form comprises two passageways, 25 mils (0.635 mm), and it had atandospirone mean release rate of 11.67 mg/hr. Accompanying FIGS. 3a and3b depict the delivery pattern for a dosage form provided by thisexample.

EXAMPLE 2

Following the procedure of Example 1, an osmotic dosage form comprisinga drug dose of 80 mg of drug was prepared to provide the followingdosage form: a drug layer comprising 50 wt % of tandospirone, 25 wt % ofpoly(ethylene oxide) comprising a 200,000 molecular weight, 19.95 wt %of poly(ethylene oxide) comprising a 300,000 molecular weight, 4.0 wt %of poly(vinyl pyrrolidone), 0.05 wt % of butyl hydroxytoluene, and 1.0wt % magnesium stearate. The push composition comprises 68.75 wt %poly(ethylene oxide) of 7,500,000 molecular weight, 25.0 wt % sodiumchloride, 5.0 wt % hydroxypropylmethylcellulose, 1 wt % ferric oxide and0.25 wt % magnesium stearate. The wall comprises 95 wt % celluloseacetate comprising 39.8% acetyl content and 5 wt % poly(ethylene glycol)of 3350 molecular weight. The dosage form comprises two 30 milsorifices, 0.762 m, and the cumulative release rate is depicted in FIG.4. In this example, the drug layer weighed 176 mg, consisting of a doseor 80 mg of tandospirone and a tandospirone overage of 8 mg.

EXAMPLE 3

The procedures of Example 1 and Example 2 are followed in this exampleto provide a dosage form comprising a total drug content of 132 mg oftandospirone, a tandospirone does of 120 mg, and a mean release rate of9.17 mg/hr of tandospirone over a 15.6 hour period of time. In thisexample, the total weight of the drug layer was 264 mg, the total weightof the push layer was 130 mg, the dosage form had a diameter of 13/32inches (10.32 mm) and 2 orifices of 30 mils (0.762 mm).

EXAMPLE 4

A dosage form is provided comprising the following: a total tandospironeof 88 mg; a drug dose of tandospirone of 80 mg; a drug layer comprising50 wt % tandospirone, 70 wt % poly(ethylene oxide) comprising a 200,000molecular weight, 4 wt % poly(vinyl pyrrolidone) of 40,000 molecularweight, 0.95 wt % magnesium stearate, and 0.05 wt % butylhydroxytoluene; the push layer weighed 174 mg and comprises 68.75 wt %poly(ethylene oxide) of 7,500,000 molecular weight, 25 wt % sodiumchloride, 6 wt % hydroxypropylmethylcellulose, 1 wt % ferric oxide, and0.25 wt % magnesium stearate; a wall comprising 95 wt % celluloseacetate comprising an acetyl content of 39.8%, and 5 wt % polyethyleneglycol. The dosage form comprises two 25 mils (0.635 mm) passageways,and a nominal T₉₀ over 14 hours means release rate of 6.1 mg/hr oftandospirone.

EXAMPLES 5 AND 6

Two dosage forms comprising a total dose of 176 mg of tandospirone wereprepared wherein both dosage forms comprised a 352 mg drug layercomprising 50 wt % tandospirone, 33.75 wt % of poly(ethylene oxide)comprising a 200,000 molecular weight, 11.25 wt % of poly(ethyleneoxide) comprising a 300,000 molecular weight, 4 wt % of poly(vinylpyrrolidone) comprising 40,000 molecular weight, and 1 wt % magnesiumstearate. The push layer was as described in Example 4. One dosage formprovided by this example comprises one passageway of 25 mils diameter(0.635 mm) and a nominal T₉₀ mean release rate of 10.820 mg/hr for 15.7hours; and the other dosage form comprises two passageways of 25 milsdiameter (0.635 mm), a nominal T₉₀, and a mean release rate of 11.128mg/hr for 15 hours.

EXAMPLES 7 AND 8

Two dosage forms were manufactured comprising a drug layer weighing 352mg and a push layer weighing 174 mg. The drug layer in one manufacturecomprises 50 wt % tandospirone hydrochloride, 25 wt % poly(ethyleneoxide) comprising a 200,000 molecular weight, 19.95 wt % poly(ethyleneoxide) comprising a 300,000 molecular weight, 4 wt %hydroxypropylmethylcellulose comprising a 11,200 molecular weight, 1 wt% magnesium stearate and 0.05 wt % of butyl hydroxytoluene. The druglayer in the other manufacture comprises 50 wt % tandospironehydrochloride, 25 wt % poly(ethylene oxide) comprising a 200,000molecular weight, 19.95 wt % of poly(ethylene oxide) comprising a300,000 molecular weight, 4 wt % poly(vinyl pyrrolidone), comprising a40,000 molecular weight, 1 wt % magnesium stearate and 0.05 wt % butylhydroxytoluene. The push layer in both manufactures comprises 68.75 wt %poly(ethylene oxide) comprising a 7,300,000 molecular weight, 25.00 wt %sodium or potassium chloride, 5 wt % a hydroxypropylmethylcellulosecomprising a 17,875 molecular weight, 1.00 wt % ferric oxide and 0.25 wt% magnesium stearate. The semipermeable wall, in both manufactures,comprises 95 wt % cellulose triacetate consisting of 39.8% acetylcontent and 5 wt % poly(ethylene glycol) of 3350 molecular weight. Thedosage form comprises two 25 mil (0.635 mm) passageways connecting thedrug layer with the exterior of the dosage form. Accompanying drawingFIG. 5 depicts the drug release over time. The dark square denotes adrug layer comprising poly(vinyl pyrrolidone) and the plain squaresdenote a drug layer comprising hydroxypropylmethylcellulose.

EXAMPLE 9

A dosage form is provided for delivering the succinimide drugsublingually, wherein the dosage form is sized, shaped and adapted forsublingual, that is subglossal blow or beneath the tongue foradministering the drug to the hypoglossal drug receptors. The sublingualdosage form for administering tandospirone to the sublingualtandospirone receiving area to a patient in need of tandospironetherapy, comprises: (a) a wall comprising a member selected from thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate and cellulosetriacetate, which semipermeable wall surrounds; (b) an internal lumen;with (c) at least one exit passageway in the wall that connects theexterior of the sublingual dosage form with the lumen; (d) a push layerin the lumen comprising an osmotic agent, that in the presence of fluidthat enters the lumen increases in volume and thereby occupies space inthe lumen; and, (e) a tandospirone layer in the lumen initially separatefrom the push layer and in initial contact with the push layer and ininitial contact with the push layer, which tandospirone layer comprisesa poly(oxyethylene) comprising a 1.75×10⁵ to 2.25×10⁵ molecular weightand a poly(oxyethylene) comprising a 2.50×10⁵ to 3.25×10⁵ molecularweight, which dosage form delivers the tandospirone composition throughthe exit to the patient at a substantially zero order rate of releaseover a period of up to 24 hours to produce a tandospirone plasma levelfor treating depressive disorders, including major depression that issingle or recurrent, bipolar disorders such as depressed depresseddepressive disorders, dysthymia, major depression with or withoutmelancholia, or cyclothymia as characterized by alternate lively anddepressed moods.

EXAMPLE 10

A dosage form is provided for delivery tandospirone buccally, comprisingthe area adjacent to, or in the direction of the check, which dosageform is sized, shaped and adapted for positioning in the buccal area ofthe mouth for administering tandospirone to buccal tandospirone drugreceptor areas, wherein the tandospirone buccal dosage form comprises:(a) a wall comprising a member selected from the group consisting ofcellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate and cellulose triacetate, which buccallyacceptable semipermeable wall surrounds; (b) an internal lumen; with (c)at least one exit passageway in the wall that connects the buccalexterior with the interior lumen of the buccal dosage form; (d) a pushlayer in the lumen comprising an osmotic agent, that in the presence ofbuccal fluid that enters the lumen increases in volume and therebyoccupies space in the lumen; and (e) a tandospirone layer in the lumeninitially separated from the push layer and in initial contact with thepush layer, which tandospirone layer comprises a poly(O--CH₂ CH₂)_(n)wherein n is 4,000 to 5,500 and a second and different poly(O--CH₂CH₂)_(n) wherein n is 6,500 to 7,400, which buccal dosage form deliversthe tandospirone composition through the exit to the patient at asubstantially zero order rate of drug delivery over a period up to 24hours to produce a tandospirone plasma level for treating depressivedisorders including major depression that is single or recurrent,bipolar disorders such as depressed depressed depressive disorders,dysthymia, major depression with or without melancholia, or cyclothymiaas characterized by alternate lively and depressed moods.

DISCLOSURE OF USE OF THE DOSAGE FORM FOR PERFORMING A METHOD OFPRACTICING THE INVENTION

An embodiment of the invention pertains to the use of the dosage formprovided by the invention in a method for delivering a drug of formula 1at a controlled rate orally to a warm-blooded animal in need of drugformula 1 therapy, wherein the use comprises the steps of: (A) admittinginto the warm-blooded animal a dosage form comprising: (1) a wallsurrounding a compartment, the wall comprising a semipermeable polymericcomposition permeable to the passage of fluid and substantiallyimpermeable to the passage of drug; (2) a drug layer in the compartmentcomprising a formulation comprising a dosage unit amount of the drug ofthe formula: ##STR5## for performing a therapeutic program; (3) a pushlayer in the compartment comprising an osmotic formulation for imbibingand absorbing fluid for expanding in size for pushing the drug of theformula from the dosage form; (4) at least one osmotic dimensionedpassageway in the wall for releasing the drug; (B) imbibing fluidthrough the semipermeable wall at a fluid rate determined by thepermeability of the semipermeable wall and the osmotic pressure acrossthe semipermeable wall causing the push layer to expand; and (C)delivering the therapeutically active drug from the dosage form throughthe exit passageway to the warm-blooded animal over a prolonged periodof time up to 24 hours. The drug to the formula is administer by themethod of the invention for treating depressive disorders, includingmajor depression - single or recurrent, bipolar disorder - depresseddepressed depressive disorders, dysthymia, major depression with ourwithout melancholia, or cyclothymia as characterized by alternate livelyand depressed moods. The drug can be in the exo form as follows:##STR6## or, the drug can be in the endo form as follows: ##STR7## orthe drug can be a mixture of the exo and the endo forms.

Dosage form 10 of this invention, as seen in the above drawing figures,can be used in a method for administering a drug by the oral route, andin another method, the dosage form can be sized and shaped foradministering a drug by the sublingual and buccal routes. The sublingualand buccal routes can be used for quicker therapy and they can be usedwhen a smaller dose of drug is needed for therapy. The latter routes canbe used as a by-pass of the first pass of hepatic metabolism of thedrug. The drug of figure (1) and (2) can be administered by thesublingual or buccal routes can be used for administering the drug forthe management of anxiolytic patients. The administration of the drugsof the formulae of this invention by the sublingual and buccal routes ofadministration is novel and nonobvious for proving the intended therapyby these routes of administration.

In summary, it will be appreciated that the present inventioncontributes to the art an unobvious dosage form that possesses practicalutility, can administer a drug at a dose metered release rate per unittime. While the invention has been described and pointed out in detailwith reference to operative embodiments thereof, it will be understoodby those skilled in the art that various changes, modifications,substitutions and omissions can be made without departing from thespirit of the invention. It is intended, therefore, that the inventionembraces those equivalents within the scope of the claims which follow.

We claim:
 1. A buccal dosage form for administering tandopsirone to thebuccal-mucosal environment of a patient in need of tandospirone therapy,wherein the buccal dosage form comprises:(a) a wall comprising a memberselected from the group consisting of cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,and cellulose triacetate, which wall surrounds; (b) an internal lumen;(c) an exit passageway in the wall that connects the buccal-mucosalenvironment with the internal lumen; (d) a push composition in thelumen, comprising an osmotically fluid-activated agent, that in theprescence of buccal-mucosal fluid that enters the lumen, increases involume and thereby occupies space in the lumen, and wherein the buccaldosage form is characterized by: (e) a buccal-mucosal compositioncomprising 1 mg to 750 mg of tandospirone, a poly(O--CH₂ CH₂)_(n)wherein n is 4,000 to 5,500, a different poly(O--CH₂ CH₂)_(n) wherein nis 6,500 to 7,400, and wherein the buccal-mucosal composition, whenadministered by the dosage form to the patient, provides tandospironefor treating depression, major depression accompanied by melancholia,dysthymia, cyclothymia and anxiolytic.